Clinical Trial Results:
A randomized, double-blind, multicenter study to establish the safety and efficacy of ceftobiprole medocaril compared with vancomycin plus aztreonam in the treatment of acute bacterial skin and skin structure infections
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Summary
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EudraCT number |
2017-001605-32 |
Trial protocol |
HU BG |
Global end of trial date |
22 Apr 2019
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Results information
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Results version number |
v2(current) |
This version publication date |
01 Jun 2023
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First version publication date |
02 May 2020
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Other versions |
v1 |
Version creation reason |
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Summary report(s) |
BPR-CS-008 Protocol Synopsis |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BPR-CS-008
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03137173 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Basilea Pharmaceutica International Ltd
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Sponsor organisation address |
Grenzacherstrasse 487, Basel, Switzerland, 4005
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Public contact |
Medical Chief Officer, Marc Engelhardt, Basilea Pharmaceutica International Ltd, +41 797010551, marc.engelhardt@basilea.com
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Scientific contact |
Medical Chief Officer, Marc Engelhardt, Basilea Pharmaceutica International Ltd, +41 797010551, marc.engelhardt@basilea.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
06 Aug 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
22 Apr 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Apr 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary and the main secondary objectives were region-specific. For submission to the U.S. Food and Drug Administration (FDA), the primary objective was to demonstrate the non-inferiority of ceftobiprole to vancomycin plus aztreonam in patients with acute bacterial skin and skin structure infections (ABSSSIs) with respect to early clinical response based on percent reduction in lesion size at 48–72 hours after first treatment in the Intent-to-Treat (ITT) population. For submission to to the European Medicines Agency (EMA), the primary objective was to demonstrate the non-inferiority of ceftobiprole to vancomycin plus aztreonam in patients with ABSSSIs, with respect to investigator-assessed clinical success at the test-of-cure (TOC) visit 15–22 days after randomization, in the co-primary ITT and Clinically Evaluable (CE) populations. This is in accordance with the guidelines from these two regulatory authorities (FDA 2013 and EMA 2014).
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Protection of trial subjects |
No additional pain or distress was caused by the use of the investigational product.
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Background therapy |
None | ||
Evidence for comparator |
The study was designed in accordance with the current U.S. FDA "Guidance for Industry, Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment" (October 2013), and the EMA "Addendum to the Guideline on the evaluation of medicinal products indicated for treatment of bacterial infections" (May 2014). The active comparator treatment, vancomycin, is the standard treatment for ABSSSI, recognized as such in current guidelines. | ||
Actual start date of recruitment |
19 Feb 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Bulgaria: 96
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Country: Number of subjects enrolled |
Hungary: 3
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Country: Number of subjects enrolled |
United States: 418
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Country: Number of subjects enrolled |
Ukraine: 162
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Worldwide total number of subjects |
679
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EEA total number of subjects |
99
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
586
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From 65 to 84 years |
89
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85 years and over |
4
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Recruitment
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Recruitment details |
Recruitment started on 19 February 2018 and ended on 22 February 2019. Patients were recruited in the following countries: Bulgaria, Hungary, Ukraine, and USA. Only male or female patients aged ≥18 years could be enrolled. | |||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Patients with an ABSSSI who received any systemic antibacterial treatment within 14 days, or topical antibacterial administration on the primary lesion within 96 hours, before first infusion of study drug were ineligible for enrollment in the study. | |||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||||||||||||||
Blinding implementation details |
The only unblinded site team member was the unblinded pharmacist. The unblinded pharmacist provided blinded and properly-labeled study medication, and was the only team member with access to treatment codes via the IWRS. Blinded treatment labels were affixed on the prepared infusion bags and corresponding documents. All pharmacy documents which could lead to potential unblinding remained secured.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Ceftobiprole ITT population | |||||||||||||||||||||||||||
Arm description |
Ceftobiprole medocaril is the water-soluble prodrug of ceftobiprole, an advanced cephalosporin that has been developed for intravenous (IV) administration. Ceftobiprole is characterised by potent, broad-spectrum antimicrobial activity against both Gram-positive and Gram-negative pathogens, including those that have developed various forms of antibacterial resistance. The recommended dose of ceftobiprole is 500 mg administered as a 2-hour IV infusion every 8 hours. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Ceftobiprole medocaril
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Ceftobiprole 500 mg was to be administered as a 2-hour IV infusion every 8 hours (with dose adjustment for renal impairment). The treatment duration was for a minimum of 5 days and a maximum of 10 days. Treatment could be extended up to 14 days if in the investigator’s opinion this was required, and the extension was approved by the sponsor’s medical monitor.
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Arm title
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Vancomycin+Aztreonam ITT population | |||||||||||||||||||||||||||
Arm description |
Vancomycin is an antibacterial agent that inhibits bacterial cell wall synthesis and alters cell-membrane permeability and RNA synthesis, with a mean half-life of 4–6 hours. The usual daily IV dose of vancomycin is 2000 mg, administered either as 500 mg every 6 hours or 1000 mg every 12 hours. Patient factors, such as age, obesity, or renal function, may require modification of the daily IV dose. Aztreonam is an antibacterial agent that acts by inhibition of bacterial cell wall synthesis. It confers selective activity against Gram-negative aerobic bacteria, and is not efficacious against Gram-positive bacteria. Aztreonam has been used in previous Phase 3 ABSSSI studies with a dose regimen of 1000 mg every 12 hours in combination with vancomycin, which lacks efficacy against Gram-negative bacteria. The requirement for aztreonam therapy was to be reassessed at the 72-hour study visit. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
Vancomycin 1000 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
The dosage regimen used for vancomycin at the study site for all patients was agreed by the investigator and the unblinded pharmacist (or delegate) before randomization. Vancomycin dose adjustment for morbidly obese and hypermetabolic patients was according to local standard of care. Vancomycin 1000 mg (or 15 mg/kg) was to be administered as a 2-hour infusion every 12 hours (with dose adjustment for renal impairment). When locally available, vancomycin trough testing (VTT) might be used by the unblinded pharmacist or delegate to adjust the vancomycin dosing. The treatment duration was for a minimum of 5 days and a maximum of 10 days. Treatment could be extended up to 14 days if in the investigator’s opinion this was required, and the extension was approved by the sponsor’s medical monitor.
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Investigational medicinal product name |
Aztreonam 1000 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Aztreonam 1000 mg was to be administered as a 0.5-hour IV infusion every 12 hours. If CLCR was < 30 mL/min (i.e., severe renal impairment), the aztreonam dosage regimen was to be adjusted. The requirement to continue aztreonam therapy beyond Day 3 was to be reassessed at the 72-hour study visit.
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Baseline characteristics reporting groups
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Reporting group title |
Ceftobiprole ITT population
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Reporting group description |
Ceftobiprole medocaril is the water-soluble prodrug of ceftobiprole, an advanced cephalosporin that has been developed for intravenous (IV) administration. Ceftobiprole is characterised by potent, broad-spectrum antimicrobial activity against both Gram-positive and Gram-negative pathogens, including those that have developed various forms of antibacterial resistance. The recommended dose of ceftobiprole is 500 mg administered as a 2-hour IV infusion every 8 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Vancomycin+Aztreonam ITT population
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Reporting group description |
Vancomycin is an antibacterial agent that inhibits bacterial cell wall synthesis and alters cell-membrane permeability and RNA synthesis, with a mean half-life of 4–6 hours. The usual daily IV dose of vancomycin is 2000 mg, administered either as 500 mg every 6 hours or 1000 mg every 12 hours. Patient factors, such as age, obesity, or renal function, may require modification of the daily IV dose. Aztreonam is an antibacterial agent that acts by inhibition of bacterial cell wall synthesis. It confers selective activity against Gram-negative aerobic bacteria, and is not efficacious against Gram-positive bacteria. Aztreonam has been used in previous Phase 3 ABSSSI studies with a dose regimen of 1000 mg every 12 hours in combination with vancomycin, which lacks efficacy against Gram-negative bacteria. The requirement for aztreonam therapy was to be reassessed at the 72-hour study visit. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Ceftobiprole ITT population
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Reporting group description |
Ceftobiprole medocaril is the water-soluble prodrug of ceftobiprole, an advanced cephalosporin that has been developed for intravenous (IV) administration. Ceftobiprole is characterised by potent, broad-spectrum antimicrobial activity against both Gram-positive and Gram-negative pathogens, including those that have developed various forms of antibacterial resistance. The recommended dose of ceftobiprole is 500 mg administered as a 2-hour IV infusion every 8 hours. | ||
Reporting group title |
Vancomycin+Aztreonam ITT population
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Reporting group description |
Vancomycin is an antibacterial agent that inhibits bacterial cell wall synthesis and alters cell-membrane permeability and RNA synthesis, with a mean half-life of 4–6 hours. The usual daily IV dose of vancomycin is 2000 mg, administered either as 500 mg every 6 hours or 1000 mg every 12 hours. Patient factors, such as age, obesity, or renal function, may require modification of the daily IV dose. Aztreonam is an antibacterial agent that acts by inhibition of bacterial cell wall synthesis. It confers selective activity against Gram-negative aerobic bacteria, and is not efficacious against Gram-positive bacteria. Aztreonam has been used in previous Phase 3 ABSSSI studies with a dose regimen of 1000 mg every 12 hours in combination with vancomycin, which lacks efficacy against Gram-negative bacteria. The requirement for aztreonam therapy was to be reassessed at the 72-hour study visit. | ||
Subject analysis set title |
Ceftobiprole CE population
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The CE population was the subset of patients in the ceftobiprole ITT population who complied with important aspects of the study until TOC visit, i.e., with no major protocol deviations.
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Subject analysis set title |
Vancomycin+Aztreonam CE population
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The CE population was the subset of patients in the Vancomycin+Aztreonam ITT population who complied with important aspects of the study until TOC visit, i.e., with no major protocol deviations.
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End point title |
Investigator-assessed clinical success at the TOC visit 15–22 days after randomization and at least 5 days after the end of treatment in the ITT population | |||||||||
End point description |
Clinical success assessed by the investigator used a four-point scale relative to the baseline assessment: cured, improved, stable, or worsened. If worsened, (e.g., bacteremia, osteomyelitis, amputation), signs and symptoms were documented as adverse events (AEs). Clinical success was defined as complete (cured) or nearly complete (improved) resolution of baseline signs and symptoms of the primary infection, such that no further antibacterial treatment was needed.
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End point type |
Primary
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End point timeframe |
15–22 days after randomization
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Statistical analysis title |
Non-inferiority test in the ITT population | |||||||||
Statistical analysis description |
Non-inferiority was assessed by the two-sided 95% confidence interval (CI) of the between-group difference (ceftobiprole minus vancomycin+aztreonam) using a 10% non-inferiority margin in the ITT population. Difference was computed using the Cochran-Mantel-Haenszel (CMH) weights method, adjusted for geographical region and actual type of ABSSSI.
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Comparison groups |
Ceftobiprole ITT population v Vancomycin+Aztreonam ITT population
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Number of subjects included in analysis |
679
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
Method |
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Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
1
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-3.5 | |||||||||
upper limit |
5.6 | |||||||||
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End point title |
Investigator-assessed clinical success at the TOC visit 15–22 days after randomization and at least 5 days after the end of treatment in the CE population | |||||||||
End point description |
Clinical success assessed by the investigator used a four-point scale relative to the baseline assessment: cured, improved, stable, or worsened. If worsened, (e.g., bacteremia, osteomyelitis, amputation), signs and symptoms were documented as AEs. Clinical success was defined as complete (cured) or nearly complete (improved) resolution of baseline signs and symptoms of the primary infection, such that no further antibacterial treatment was needed.
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End point type |
Primary
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End point timeframe |
15–22 days after randomization
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Statistical analysis title |
Non-inferiority test in the CE population | |||||||||
Statistical analysis description |
Non-inferiority was assessed by the two-sided 95% CI of the between-group difference (ceftobiprole minus vancomycin+aztreonam) using a 10% non-inferiority margin in the CE population. Difference was computed using the CMH weights method, adjusted for geographical region and actual type of ABSSSI.
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Comparison groups |
Ceftobiprole CE population v Vancomycin+Aztreonam CE population
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Number of subjects included in analysis |
576
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
Method |
Cochran-Mantel-Haenszel | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
2.7
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-0.3 | |||||||||
upper limit |
5.6 | |||||||||
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End point title |
Early clinical response 48–72 hours after start of treatment in the ITT population | |||||||||
End point description |
The secondary endpoint was the early clinical response in the ITT population, based on the percent reduction in lesion size at 48– to 72 hours compared to baseline, measured in patients who did not receive rescue therapy and were alive.
Early clinical response 48–72 hours after start of treatment met all of the following criteria:
1. ≥ 20% reduction from baseline in the area of the primary lesion
2. Survival for ≥ 72 hours from the time of administration of the first dose of study drug
3. No use of concomitant systemic antibacterial treatments, or topical antibacterial administration on the primary lesion before or on the latest lesion measurement done within 48–72 hours after the first dose of study drug
4. No additional unplanned surgical procedure for the ABSSSI after start of therapy and before or on the day of latest lesion measurement done within 48–72 hours after the first dose of study drug.
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End point type |
Secondary
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End point timeframe |
48–72 hours after start of treatment
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Statistical analysis title |
Non-inferiority test in the ITT population | |||||||||
Statistical analysis description |
Non-inferiority was assessed by the two-sided 95% CI of the between-group difference (ceftobiprole minus vancomycin+aztreonam) using a 10% non-inferiority margin in the ITT population. Difference was computed using the CMH weights method, adjusted for geographical region and actual type of ABSSSI.
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Comparison groups |
Ceftobiprole ITT population v Vancomycin+Aztreonam ITT population
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Number of subjects included in analysis |
679
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
Method |
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Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
3.3
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-1.2 | |||||||||
upper limit |
7.8 | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Relevant change / worsening of a patient’s status after informed consent (before start of first study-drug infusion) was recorded in medical history. From start of first dosing to and including the last follow-up visit, these data were recorded as AEs.
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Adverse event reporting additional description |
Once an AE was detected, it was to be proactively followed up at each visit (or more frequently if necessary) for any changes in severity, relationship to the study drug, interventions required for treatment, and the event’s outcome. Serious adverse events (SAEs) were to be additionally reported and recorded on SAE report forms.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22
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Reporting groups
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Reporting group title |
Vancomycin+Aztreonam (Safety population)
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Reporting group description |
Safety population: all randomized patients who received at least one dose of study drug. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Ceftobiprole (Safety population)
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Reporting group description |
Safety population: all randomized patients who received at least one dose of study drug. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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11 Jul 2018 |
1. To comply with Competent Authority recommendation, the temperature ranges for the definition of fever was specified in inclusion criteria according to the methods of measurement (inclusion criterion 3b).
2. During medical monitoring, it was noted that a high proportion of patients enrolled in the study were illicit drug users. The sponsor therefore limited the further enrollment of illicit drug users in the study to better support generalisation of the study results in the context of clinical practice. In addition, a subgroup analysis was added to include illicit drug use as a pre-specified subgroup. The following exclusion criterion was added: "Patients with illicit drug use within 12 months of screening, including heroin, other opioids (unless prescribed for medical reasons unrelated to heroin substitution), cocaine / crack cocaine, and amphetamine/methamphetamine. Exception: Cannabis use."
3. Delafloxacin and meropenem/vaborbactam were added to the protocol list of antibiotics meeting the criterion of a half-life ≤ 12 hours.
4. Clarification was added of the circumstances in which the re-administration of aztreonam was permitted at any point during the study treatment period.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
